Homopolymers of glycolide and lactide have been extensively studied and reported in literature. Such polymers have received wide acceptance in pharmacological applications due to their biodegradability and non-toxicity in vivo (see e.g., Kulkarni et al., “Poly(lactic acid) for surgical implants,” Technical Rep. 6608, Walter Reed Army Medical Center, Washington, D.C., 1966). Copolymers of glycolide and lactide have also been used in medical applications due to an improvement in polymeric properties over the homopolymers. For example, copolymers of lactide and glycolide are less crystalline and the intermediate copolymeric compositions are more susceptible to hydrolytic attack than the homopolymers. Miller et al. reported a 10-fold increase in degradation on moving from homopolymers to copolymers of lactide and glycolide (Miller et al., “Degradation rates of oral resorbable implants (polylactates and polyglycolates): Rate modification with changes in PLA/PGA copolymer ratios,” J. Biomed. Mater. Res., 11:711-719, 1977).
It was noticed that hydrolysis rates of lactide-glycolide copolymers typically increase above the polymer glass transition temperature. Crystallinity and polymer chain orientation were shown to retard degradation. Irradiation, used for sterilization, was also shown to accelerate degradative processes. Thus, many have studied the effects of monomer ratios and different additives on lactide-glycolide copolymers in efforts to tailor specialty compositions with desirable properties.
It is often desired to prepare viscous formulations of polymers for drug delivery. In one example, ATRIX ATRIGEL™ is a poly(lactide-glycolide) polymer that can be prepared as a viscous liquid. However, it must be dissolved in relatively large quantities of organic solvents (like N-methylpyrrolidone) in order to form the viscous formulation. Typical polymer concentrations in the solvent are on the order of about 10% to 50%. Another high viscosity injectable is Durect's SABER™, which is a sucrose acetate isobutyrate that is a non-polymeric high-viscosity liquid that thins-out dramatically with the addition of small quantities of solvent (like ethanol). This makes it attractive in that only small quantities of solvent are needed to bring the viscosity of the material down to practical, injectable levels. However, the SABER™ material itself has few factors or variables that can be manipulated in order to adjust the attributes of the material as a platform-based technology.
Another drug-delivery platform involves polymeric micelles containing biodegradable, hydrophobic blocks. Polymeric micelles have been described where block copolymers comprising polycaprolactone (PCL) are the hydrophobic polymer core-forming components(s) and polyethylene glycol are the hydrophilic shell-forming components(s) (see e.g., U.S. Pat. No. 6,469,132). Such micelles can be particularly suited to carrying or solubilizing hydrophobic or lipophilic drugs having affinity towards (and that partition into) the hydrophobic cores of these particles.
Of the hydrophobic biodegradable polymers (such as polyesters based on lactide or caprolactone), PCL is often used because longer chain-length of the caprolactone produces a more hydrophobic polymer. However, PCL as a biodegradable, hydrophobic block suffers in that it is a crystalline to semi-crystalline polymer; PCL has a melting point of about 60° C. Crystallinity within the core of the polymeric micelle can be disadvantageous in that the crystalline regions are highly organized, tightly-structured areas that provide no room or space for carrying a drug load. Therefore, crystallinity will lower the drug-loading capacity of the resulting polymeric micelle. Another biodegradable polymer known to contain highly crystalline structures is poly(L-lactide).
What are needed are new biocompatible polymer compositions that can be viscous liquids or polymeric micelles and that have other unique properties suitable for certain pharmaceutical and medical applications. Compositions that are viscous liquids without the need for organic solvents or without large amounts of solvents are desired. It is also desired to have polymers with hydrophobic biodegradable core-forming blocks for preparing polymeric micelles and yet that do not also suffer from the disadvantages associated with the crystallinity of PCL. Also desired are compositions that can be easily modified to provide variability in terms of release, duration, and performance. The compositions and methods disclosed herein meet these and other needs.